Diffuse interstitial myocardial fibrosis is a prominent feature of maladaptive interstitial remodeling of the extracellular matrix, and is associated with myocardial dysfunction and heart failure. We propose to use contrast-enhanced magnetic resonance imaging (MRI) to measure the extracellular volume fraction as a marker of expansion of the extracellular matrix. An expansion of the extracellular matrix is invariably linked to an increase of total collagen volume fraction, an accepted histological marker of fibrosis. Our approach is based on quantitative pre- and post-contrast cardiac T1 imaging, and the estimation of the myocardial partition coefficient for an extracellular gadolinium-based contrast agent (;Gd). The hypothesis' are: a) the extracellular volume fraction is significantly elevated in patients with pressure-overloaded ventricles and myocardial hypertrophy, compared to healthy controls, but lower than in myocardial scar or replacement fibrosis in patients with ischemic heart disease; b) differences of the extracellular volume fraction between healthy controls and patients with elevated interstitial fibrosis become more significant by correcting for the effects of the transcytolemmal water exchange; c) the extracellular volume fraction correlates with the total collagen volume fraction, which will be tested in a mouse model of interstitial fibrosis by INOS inhibition; and d) ;Gd can be determined rapidly and accurately by dynamic imaging after a contrast bolus injection, using a tracer kinetic model-based analysis to obtain a ;Gd estimate which is independent of the levels of myocardial blood flow and the capillary permeability surface area product. The research plan is based on MRI studies in patients diagnosed with aortic stenosis with no previous history of coronary disease, who will undergo aortic valve replacement. Healthy, age- and gender-matched volunteers will allow us to define the normal range of the fibrosis-related MRI index. Our long term goal is the development of a sensitive MRI-based marker of extracellular matrix remodeling and diffuse interstitial fibrosis which could reduce the need for cardiac tissue biopsies. We anticipate that the successful development of such an MRI-based marker will have important health benefits for risk stratification, prognosis and treatment in patients where the progression of myocardial fibrosis could lead to myocardial dysfunction, and ultimately heart failure. PUBLIC HEALTH RELEVANCE: Excessive fibrosis within the heart muscle as a result of aging, or of heart disease contributes to a stiffening of the ventricular walls, a decline of the pump-function of the heart, dilation of the ventricles, and ultimately also to heart failure. We propose the development of a novel method for assessment of diffuse fibrosis in the heart muscle with magnetic resonance imaging.